期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 12, 页码 2041-2056出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20150186
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资金
- National Institutes of Health [3R01AI07469905, 3R01AI07469905S]
- National Research Service Award (National Institute of Allergy and Infectious Diseases, Ruth Kirschstein Predoctoral Fellowship) [F31 AI084500-01]
- Howard Hughes Medical Institute Gilliam Fellowship
- Howard Hughes Medical Institute International Student Research Fellowship
- Howard Hughes Medical Institute
The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.
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